Enhanced affinity ligands

Abstract

The present invention relates to ligands, nanocrystal complexed with said ligands and their use for bio-imaging.

1 . A ligand which is a copolymer synthetized from at least 3 monomers, said monomers being:
 one anchoring monomer A comprising a first moiety M A  having affinity for the surface of a nanocrystal,   one hydrophilic monomer B comprising a second moiety M B  having a high water solubility, and   one functionalizable monomer C comprising a third moiety M C  having a reactive function.   
     
     
         2 . The ligand according to  claim 1 , wherein the copolymer is a terpolymer having the following formula (III):
   (A) x (B) y (C) z ,   
       wherein
 monomers A, B and C are as defined in  claim 1 ; and 
 each of x, y and z is independently a positive integer, preferably an integer ranging from 1 to 498. 
 
     
     
         3 . The ligand according to  claim 2 , wherein each of monomers B and C is individually selected from methacrylate monomers and methacrylamide monomers. 
     
     
         4 . The ligand according to  claim 1 , wherein said first moiety M A  having affinity for the surface of a nanocrystal is a thiol moiety, a dithiol moiety, an imidazole moiety, a catechol moiety, a pyridine moiety, a pyrrole moiety, a thiophene moiety, a thiazole moiety, a pyrazine moiety, a carboxylic acid or carboxylate moiety, a naphthyridine moiety, a phosphine moiety, a phosphine oxide moiety, a phenol moiety, a primary amine moiety, a secondary amine moiety, a tertiary amine moiety, a quaternary amine moiety, an aromatic amine moiety, or a combination thereof. 
     
     
         5 . The ligand according to  claim 1 , wherein said second moiety M B  having a high water solubility is a zwitterionic moiety such as for example an aminocarboxylate, an aminosulfonate, a carboxybetaine moiety wherein the ammonium group may be included in an aliphatic chain, a five-membered cycle, a five-membered heterocycle comprising 1, 2 or 3 further nitrogen atoms, a six-membered cycle, a six-membered heterocycle comprising 1, 2, 3 or 4 further nitrogen atoms, a sulfobetaine moiety wherein the ammonium group may be included in an aliphatic chain, a five-membered cycle, a five-membered heterocycle comprising 1, 2 or 3 further nitrogen atoms, a six-membered cycle, a six-membered heterocycle comprising 1, 2, 3 or 4 further nitrogen atoms, a phosphobetaine wherein the ammonium group may be included in an aliphatic chain, a five-membered cycle, a five-membered heterocycle comprising 1, 2 or 3 further nitrogen atoms, a six-membered cycle, a six-membered heterocycle comprising 1, 2, 3 or 4 further nitrogen atoms, a phosphorylcholine, a phosphocholine moiety, and combinations thereof or a PEG moiety. 
     
     
         6 . The ligand according to  claim 1 , wherein said third moiety M C  having a reactive function is selected from any moiety having an amine group such as a primary amine group, any moiety having an azido group, any moiety having an alkenyl group, any moiety having an acidic function, any moiety having an alcoholic group, any moiety having a thiol group, any moiety that can form a non covalent bond with a selective binding counterpart, said moiety being for example biotin, a nucleic acid, FK506, or an antibody. 
     
     
         7 . The ligand according to  claim 1 , wherein said first moiety M A  having affinity for the surface of a nanocrystal is dithiol moiety or an imidazole group, preferably a propane-1,3-dithiol, more preferably a propan-1-yl-1,3-dithiol moiety. 
     
     
         8 . The ligand according to  claim 1 , wherein said second moiety M B  having a high water solubility is a zwitterionic group or a poly(alkylene oxide) group, preferably a sulfobetaine group or a poly(ethylene glycol) group. 
     
     
         9 . The ligand according to  claim 1 , wherein said third moiety M c  having a reactive function comprises a carboxylic acid, an activated carboxylic acid, an amino or an azido group. 
     
     
         10 . The ligand according to  claim 1 , wherein the ligand is a terpolymer synthetized from:
 at least one monomer A selected from 4-vinylimidazole and 5-(1,2-dithiolan-3-yl)-N-(3-methacrylamidopropyl)-pentanamide;   at least one monomer B selected from poly(ethylene glycol)methylether methacrylate and 3-[3-methacrylamidopropyl)dimethylammonio]-propane-1-sulfonate; and   at least one monomer C selected from methacrylic acid, N-(3-aminopropyl)methacrylamide and N-(aminotetra(ethylene glycol)ethyl methacrylamide.   
     
     
         11 . The ligand according to  claim 1 , which is a block copolymer or a statistic copolymer. 
     
     
         12 . The ligand according to  claim 1 , wherein the ratio x/y/z is selected from 20/10/70, 20/40/40, 20/50/30, 25/25/50, 30/40/30 and 30/50/20. 
     
     
         13 . The ligand according to  claim 1 , wherein x+y+z ranges from 5 to 750, preferably from 10 to 100, more preferably from 11 to 30. 
     
     
         14 . The ligand according to  claim 1 , wherein the ligand has molecular weight ranging from more than 0 to 10 MDa, preferably from 0.5 kDa to 100 kDa, more preferably from 1 kDa to 50 kDa. 
     
     
         15 . The ligand according to  claim 1 , being functionalized with at least one molecular probe and/or targeting group. 
     
     
         16 . A nanocrystal being complexed with at least one ligand according to  claim 1 . 
     
     
         17 . The nanocrystal according to  claim 16 , wherein said nanocrystal is a 0D, 1D, or 2D nanocrystal , preferably a nanosheet, a nanorod, a nanoplatelet, a nanoplate, a nanoprism, a nanowall, a nanodisk, a nanoparticle, a nanowire, a nanopowder, a nanotube, a nanotetrapod, a nanoribbon, a nanobelt, a nanoneedle, a nanocube, a nanoball, a nanocoil, a nanocone , a nanopiller, a nanoflower , or a quantum dot. 
     
     
         18 . A water-soluble composition comprising at least one nanocrystal being complexed with at least one ligand according to  claim 1 . 
     
     
         19 . Use of the water-soluble composition of  claim 18  for bioimaging, biotargeting, medical imaging or biosensing. 
     
     
         20 . Use of the nanocrystal of  claim 16  for bioimaging, biotargeting, medical imaging or biosensing.